Intermolecular [3+3] ring expansion of aziridines to dehydropiperi-dines through the intermediacy of aziridinium ylides

Josephine Eshon, Kate A. Nicastri, Steven C. Schmid, William T. Raskopf, Ilia A. Guzei, Israel Fernández and Jennifer M. Schomaker ()
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Josephine Eshon: University of Wisconsin
Kate A. Nicastri: University of Wisconsin
Steven C. Schmid: University of Wisconsin
William T. Raskopf: University of Wisconsin
Ilia A. Guzei: University of Wisconsin
Israel Fernández: Universidad Complutense de Madrid
Jennifer M. Schomaker: University of Wisconsin

Nature Communications, 2020, vol. 11, issue 1, 1-8

Abstract: Abstract The importance of N-heterocycles in drugs has stimulated diverse methods for their efficient syntheses. Methods that introduce significant stereochemical complexity are attractive for identifying new bioactive amine chemical space. Here, we report a [3 + 3] ring expansion of bicyclic aziridines and rhodium-bound vinyl carbenes to form complex dehydropiperidines in a highly stereocontrolled rearrangement. Mechanistic studies and DFT computations indicate that the reaction proceeds through formation of a vinyl aziridinium ylide; this reactive intermediate undergoes a pseudo-[1,4]-sigmatropic rearrangement to directly furnish heterocyclic products with net retention at the new C-C bond. In combination with asymmetric silver-catalyzed aziridination, enantioenriched scaffolds with up to three contiguous stereocenters are rapidly delivered. The mild reaction conditions, functional group tolerance, and high stereospecificity of this method are well-suited for appending piperidine motifs to natural product and complex molecules. Ultimately, our work establishes the value of underutilized aziridinium ylides as key intermediates for converting small, strained rings to larger N-heterocycles.

Date: 2020
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DOI: 10.1038/s41467-020-15134-x

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